A GLP-1 (glucagon-like peptide-1) is known as a hormone which is secreted from a digestive tract by food intake and acts on the pancreas to stimulate glucose-dependent insulin secretion. In Type 2 diabetic patients, it is reported that responsiveness to this GLP-1 is maintained, while the production of GLP-1 is impaired. It is expected that development of a GLP-1 agent will lead to the application of the agent to a therapeutic agent for diabetes as an insulin secretion promoter to compensate the lack of the GLP-1.
However, the active substance of the GLP-1 is a polypeptide of GLP-1 (7-36) amide or GLP-1 (7-37), which is digested and degraded by a digestive enzyme in the gastrointestinal tract and does not function sufficiently, when the GLP-1 is taken orally. Therefore, in the present state, intravenous injection by instillation or subcutaneous injection is attempted in clinical practice. Moreover, it is also reported that: the GLP-1 is also subjected to degradation by a dipeptidylpeptidase IV (DPP-IV) which exists in blood and tissues, so the active half-life time of the GLP-1 is so short as 1-2 min, and GLP-1 is easily excreted from the kidney, so its half-life time in blood is within 5 min, all of which prevents the GLP-1 from clinical application. Hence, a GLP-1 derivative with a long half-life which is not easily degraded has been developed. For instance, followings are included: the 8th position of amino acid substituted derivative (Diabetologia 41: 271-278 (1998); Biochem 40: 2860-2869 (2001)), an amino acid modulator at N- and C-terminals (WO9808871 etc.), a derivative in which Arg is substituted for the amino acid at its 34th position and its 26th position of Lys is introduced with lipophilic group (WO0007617), and a derivative by amino acid substitution covering all over the sequence (WO9943705 and WO9111457). Further, development of a sustained-release injection preparation which is subcutaneously absorbed slowly, etc. has been performed. However, as they are injection preparations, considering the burden to patients, a GLP-1 to be administered via an alternative route other than injection has been longed.
Production of pharmaceuticals, clinical diagnostics and industrial materials using genetic engineering technique has greatly contributed to the actual industrial world already, among which substance production systems are particularly widely utilized where cultured cells of microorganisms or mammals are used as host cells. However, culture of these cells requires culture facilities and culture media in completed sterile environment, which causes high cost. In addition, mammal cells cannot be used as hosts without involving the risk of contamination of virus which is harmful to human body. Consequently, substance production systems using cheap and safe transgenic plants have been developed instead of substance production systems by culture of cells of microorganisms or mammals. For instance, generation of transgenic plants producing: a high-molecular compound such as biodegradable polyester (e.g. Japanese Laid-Open Patent Application No. 2002-262886), a protein such as a vaccine (e.g. G. Jaeger et al., Eur. J. Biochem. 259, 426, 1999) and lactoferrin (D. Chong et al., Transgenic. Res. 9, 71, 2000), and a peptide such as enkephalin (Japanese-Laid Open Patent Application No. 2000-106890), has been reported so far.
With regard to transgenic plants, production of a functional substance being beneficial to human body in edible parts of the plants e.g. seeds of Glycine max or Oryza sativa, or vegetable leaves, allows the intended substance to be taken orally into human body directly without an extraction process for them. Further, for seeds, preservation or transportation in facility with refrigerating device is not required, while it can be steadily stored for long time at room temperature. In addition, even when the intended substance is extracted, it can be easily purified, because, unlike leaves, the contamination of phenolic substances seldom occurs with seeds. Accordingly, a seed has been regarded as an ideal organ to produce the intended genetic product, and generation of seeds which produced: proteins such as glycinin (T. Katsube et al., Plant. Physiol. 120, 1063, 1999), enzymes such as (1,3-1,4)-β-glucanase (H. Horvath et al., Proc. Nathl. Acad. Sci. USA., 97, 1914, 2000), and peptides such as enkephalin (D. Chong et al., Transgenic. Res., 9, 71, 2000) has been reported so far.